The objective of this project is to elucidate mechanisms by which the human immunodeficiency virus (HIV) induces changes in ion transport across the plasma membrane, and the effect of those changes on cell function and cytopathology in CD4+ lymphocytes, neurons and astroglial cells. Our specific aims are designed to show that first, HIV proteins NEF gp41 and gp120 alter cation transport across the plasma membrane by specific interaction with ion transport systems, or function as cation channels once inserted into the host plasma membrane. Second, the HIV- induced changes in cation plasma membrane transport lead to impairment of specific functions of the different cell types by the same mechanism. Thus, dysfunctions of neurons and astrocytes involved in the AIDS encephalopathy can be caused without viral infection of those cells via import of viral proteins into the CNS. Infection by many different lytic viruses, including HIV lead to a change in intracellular monovalent cations via changes in the activity of cation transport systems or changes in membrane permeability. In picornavirus and alphavirus infection, these cation alterations cause a number of events favoring virus replication and virus production in infected cells, and also lead to termination of host cell protein synthesis and cytopathology. Our preliminary results suggest that HIV-derived proteins/peptides alter IL-2 production by CD4+ lymphocytes due to selective inhibition of plasma membrane K+ channels. We have evidence that HIV encodes proteins with structural similarity to (i) scorpion toxins,, i.e., NEF, and gp120, and (ii), the HIV TM protein (gp41) has a similar structure to pore forming subunits of Na+ and K+ channels. Thus, like scorpion toxins, NEF and gp120 peptides may modulate existing Na+ and K+ channel activity or, new cation pores may be formed by gp41 peptides in the host cell plasma membrane. An increase in the activity of the Na+, K+-ATPase in HIV- infected CD4+ lymphocytes is consistent with an HIV-induced increase in the intracellular Na+ concentration. Thus, modulation of cation transport by such HIV proteins/peptides in astrocytes and neurons may be one key to the pathogenesis of AIDS encephalopathy. The intended investigations rationalize alterations in ion transport as a mechanism of action by which HIV proteins cause cytopathology responsible for both immunodeficiency and neurological abnormalities in HIV infection. This proposal provides new insight into the pathogenesis of AIDS and may foster development of new therapeutic approaches including modulation of specific cation transport systems.